CD73 or ecto-5′-nucleotidase (5′-NT) is expressed in a number of tissues, is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) linkage, has ecto-enzyme activity and plays a role in signal transduction. The primary function of CD73 is to convert extracellular nucleotides (e.g., 5-AMP) to their corresponding nucleosides (e.g., adenosine). CD73 produces nucleosides, particularly adenosine, in the extracellular space, and is thought to modulate neuronal signaling, vascular perfusion, drug metabolism and immune responses, as well as to have anti-inflammatory and immunosuppressive capabilities.
Adenosine is an endogenous modulator of diverse physiological functions, including the cardiovascular system (as a vasodilator and cardiac depressor), the central nervous system (CNS) (inducing sedative, anxiolytic and antiepileptic effects), the respiratory system (inducing bronchoconstriction), the kidney (having biphasic action; inducing vasoconstriction at low concentrations and vasodilation at high doses), fat cells (inhibiting lipolysis), platelets (as an antiaggregant), and the immune system, where extracellular adenosine acts on a variety of immune cells and mediates anti-inflammatory effects. Adenosine also promotes fibrosis (excess matrix production) in a variety of tissues.
CD73 is highly expressed on the surface of several types of cancer cells and immunosuppressive cells, including T regulator cells (Tregs) and myeloid-derived suppressor cells (MDSCs). ATP, released in high quantity from malignant cells succumbing to chemotherapy or other stressful conditions, is rapidly converted into adenosine, which accumulates in the tumor microenvironment. By activating adenosine receptors, intratumoral adenosine favors the escape of cancer cells from immune surveillance, hence promoting tumor progression. Targeting CD73 represents a potential strategy to increase the efficacy of anticancer therapy and offers new therapeutic strategies to limit tumor progression and treat a variety of cancers. Higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, resistance to chemotherapy, and metastasis, and with shorter patient survival time in cancer, including breast cancer. CD73 inhibitors can be used to control tumor progression and metastasis.
Because inhibition of CD73 results in decreased adenosine, CD73 inhibitors can be used for the treatment of diseases or disorders mediated by adenosine and its actions on adenosine receptors, including A1, A2A, A2B and A3. Thus, CD73 inhibitors can be used for enhancing immune responses, enhancing immunization, and increasing inflammation, as well as for treating a wide range of conditions, including neurological, neurodegenerative and CNS disorders and diseases, including depression and Parkinson's disease, cerebral and cardiac ischaemic diseases, sleep disorders, fibrosis, immune and inflammatory disorders, and cancer.
For reviews on the role of adenosine and CD73 in immunity, inflammation and cancer, see Antonioli, et al., 2013, Nature Rev., 13:842-857; Regateiro et al., 2012, Clin. Exp. Immunol., 171:1-7; Sorrentino et al., 2013, OncoImmunol., 2:e22448, doi:10.4161/onci.22448; and Allard et al., 2012, J. Biomed. Biotechnol., article ID 485156, 8 pages, doi:10.1155/2012/485156.
In light of the role that CD73 plays in disease pathogenesis, there is a need for new inhibitors of CD73 for the treatment of diseases including cancer.